期刊
STEM CELL REPORTS
卷 13, 期 2, 页码 366-379出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2019.06.004
关键词
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资金
- German Research Foundation (DFG) [EXC 62/2, ZW64/4-1, KFO311, ZW64/7-1]
- German Ministry for Education and Science (BMBF) [13N14086, 01EK1601A, 01EK1602A]
- StemBANCC (Innovative Medicines Initiative joint undertaking) from the European Union's Seventh Framework Programme (FP7/2007-2013) [115439-2]
- EFPIA companies
- European Union H2020 program [66724]
- Joachim Herz Stiftung
- MHH Hannover (HiLF grant)
- German Research Foundation [DFG TK1187/21-1]
Aiming at clinical translation, robust directed differentiation of human pluripotent stem cells (hPSCs), preferentially in chemically defined conditions, is a key requirement. Here, feasibility of suspension culture based hPSC-cardiomyocyte (hPSC-CM) production in low-cost, xeno-free media compatible with good manufacturing practice standards is shown. Applying stirred tank bioreactor systems at increasing dimensions, our advanced protocol enables routine production of about 1 million hPSC-CMs/mL, yielding similar to 1.3 x 10(8) CM in 150 mL and similar to 4.0 x 10(8) CMs in 350-500 mL process scale at >90% lineage purity. Process robustness and efficiency is ensured by uninterrupted chemical WNT pathway control at early stages of differentiation and results in the formation of almost exclusively ventricular-like CMs. Modulated WNT pathway regulation also revealed the previously unappreciated role of ROR1/CD13 as superior surrogate markers for predicting cardiac differentiation efficiency as soon as 72 h of differentiation. This monitoring strategy facilitates process upscaling and controlled mass production of hPSC derivatives.
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